Epileptic phenotypes in children with respiratory chain disorders


Address correspondence to Dr. Isabelle Desguerre, M.D., Hôpital Necker, Assistance Publique-Hôpitaux de Paris, 149 Rue de Sèvres, 75450 Paris Cedex 15, France. E-mail: isabelle.desguerre@nck.aphp.fr


Purpose:  Epilepsy is a commonly reported but rarely described clinical hallmark of mitochondrial respiratory chain defects (RCDs) with encephalopathy.

Methods:  From 1990–2006 we collected data about 56 children with RCD (single, n = 24 or multiple, n = 20 mitochondrial complex deficiencies; mtDNA mutation, n = 11; mtDNA depletion n = 10 of 21; and nuclear gene mutation n = 11). Epileptic features were reviewed retrospectively.

Results:  First seizures were frequently (47 patients, 82.5%) preceded by failure to thrive, psychomotor delay, ataxia, or multisystemic dysfunction. Sixty percent of the patients had several seizure types. Six age-related epilepsy phenotypes could be identified: status epilepticus complicating neonatal multivisceral deficiency (2 patients), neonatal myoclonic encephalopathy (3 patients), infantile spasms (8 patients), refractory or recurrent status epilepticus (21 patients), epilepsia partialis continua (4 patients), and myoclonic epilepsy (18 patients). Except for infantile spasms, epilepsy was difficult to control in most patients (95%). Valproate was administered to 25 patients, one of whom developed acute liver failure 6 days later. Twenty-two patients (45%) died, half of them within 9 months from the onset of epilepsy.

Discussion:  In RCD, epilepsy is not only difficult to control but its occurrence often indicates a severe turn in the course of the disease. For one-third of the patients, classical biochemical measures failed to reveal any abnormality and RCD could be detected in the liver only.

Mitochondrial respiratory chain defects (RCDs) often exhibit multiorgan involvement, affecting mainly tissues with high-energy requirements such as the brain. Epilepsy is frequent in children with mitochondrial diseases, since the prevalence was 34% in one series including pyruvate dehydrogenase deficiency (Debray et al., 2007). Among 31 adults and children, Canafoglia et al. (2001) found predominant partial motor seizures with focal or multifocal electroencephalography (EEG) epileptiform activity. However, clinical and EEG characteristics are rarely described in children. A single series of 48 pediatric patients with epilepsy is on record that shows a wide variety of epilepsy types ranging from Ohtahara syndrome to partial epilepsy, and in which generalized epilepsies were predominant (84%) (Lee et al., 2008).

The epilepsy pattern has been described in three clinical conditions. Patients with myoclonic epilepsy with ragged-red fibers (MERRF) present across all ages, with myoclonic seizures as the main feature (Jaksch et al., 1998). Although epilepsy may affect patients with encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS syndrome), seizures rarely become a serious problem in childhood (Hirano & Pavlakis, 1994). Indeed, typical mitochondrial syndromes with specific epileptic profile caused by mutations in mitochondrial DNA (mtDNA) are rarely diagnosed in childhood except for the T8993G mutation (MT-AP6), associated with infantile spasms as a single seizure type (Desguerre et al., 2003). Shah et al. (2002) also found mitochondriopathies to be an overlooked cause of infantile spasms. Acute liver failure with refractory status epilepticus (usually called Alpers syndrome) has been related to mitochondrial depletion due to POLG1 mutations (Tzoulis et al., 2006).

Therefore, the RCD spectrum in children encompasses a wide variety of epilepsy phenotypes. However, data are scarce regarding circumstances of discovery, course, phenotypes according to age, and response to treatment. We studied a series of 56 children to determine the spectrum of epilepsy features, strategy for diagnosis, range of prognosis, and possible pathophysiologic mechanisms of the neurologic involvement.

Patients and Methods

All patients identified over a period of 16 years (1990–2006) in our units of pediatric neurology, metabolism, and genetics as having the combination of epilepsy and definite RCD were included in this study. As suggested by Wolf and Smeitink (2002), the diagnosis of RCD was suspected on clinical presentation (muscular, central nervous system, multisystemic involvement), metabolic findings [lactates and pyruvate in blood or cerebrospinal fluid (CSF) and tricarboxylic acid (TCA) cycle intermediates in urine) and suggestive lesions on magnetic resonance imaging (MRI) or lactate peaks on H-MR spectroscopy (H-MRS). RCD was confirmed on the basis of enzymatic parameters (polarography and spectrophotometry) measured on muscle, liver, or skin, and on molecular investigations involving mtDNA (mutation, depletion) and nuclear genes. We recorded age and circumstances of RCD diagnosis.

A review of clinical, electroencephalography (EEG), imaging, biochemical, and genetic records was conducted. Data used for the characterization of epilepsy were the history given by parents and caretakers, with specific attention to seizure types [according to the 1989 Commission on Classification and Terminology of the International League Against Epilepsy(1981)] and frequency, course, and response to medication. Standard EEG was recorded in all patients and video-polygraphy monitoring was available in 40 patients. All patients underwent brain imaging, MRI in most patients (55 patients).

Biochemical investigations were rarely contributory: Lactate levels were elevated in the blood for only five patients, whereas 19 of 35 patients who underwent lumbar puncture had elevation of CSF lactate without hyperlactacidemia.

In 18 patients, muscle biopsy was not contributory and the proper diagnosis could be established only on the basis of liver biopsy findings. Most patients had deficits of the respiratory chain including multiple deficits (16), complex IV deficit (14), complex I deficit (13), and complexes II (2) and III (2) deficits, whereas two had quinone deficit (Table 1). mtDNA depletion was searched in 19 patients. It was positive for 9 of 11 patients in the liver and for 1 of 14 in the muscle (mtDNA copy number reduced to <25% of control values). Molecular findings consisted of mitochondrial DNA mutations in 11 patients (6 MT-AP6, 2 MT-ND3, 1 MT-TK, 1 MT-ND5, and 1 MT-TL1) and nuclear gene mutation in 12 (5 POLG1, 2 SDH-A, 2 CABC1, and 3 PEO1) (Ruiz-Pesini et al., 2007). POLG and PEO1 were reported elsewhere (Sarzi et al., 2007a,b).

Table 1.   Characteristics of the 56 patients
PatientType of epilepsyAge of onset (months)Hepatic disorderUse of VPACSF lactate mmoles/lMRIEnzymatic deficitMtDNA depletion (tissue analyzed)Molecular genetic
  1. Column 1: Demography: F, female; M, male; +, dead; nb, number of patients in a given family.

  2. Column 2: Epilepsy: CEE, congenital epileptic encephalopathy; EPC, epilepsia partialis continua; ME myoclonic epilepsy; PE, partial epilepsy; RS, refractory status.

  3. Column 5: VPA, sodium valproate.

  4. Column 6: N, normal; ND, not determined.

  5. Column 7: Magnetic resonance imaging (MRI): BG, basal ganglia; BS, brainstem; CA, cortical atrophy; CA++, Major cortical atrophy; Ce A, cerebellar atrophy; DN, dentate nucleus; WM, white matter.

  6. Column 8: Enzymatic deficit in RCD CI complex I, CII complex II, CIII complex III, C IV complex IV, CV complex V; multiple for multiple deficit of respiratory chain; L if RCD is only identified in liver.

  7. Column 9: Presence of mtDNA depletion in various tissues L, Liver; Mus, muscle.

  8. Column 10: Genes and identified mutations from the genome data base MITOMAP.

1M+Neonat status2 daysYesNoNDBGMultiple  
2M+Neonat status6 daysYesNoNDNDMultiple30% (Mus) 
3FCEE/SBurst1NoNo3.4CA, CeACIV110% (Mus) 
4FCEE/MultiF1NoYesNCA++, WMCI  
5F(1)CEE8 daysNoNoNCA++CIV (L)  
7M+West6NoNoNDCA, DNCI  
8MWest/ ME2NoYesNCA, WMCII  
9M(1)West/PE2NoNoNCA+CIV (L) SDH-A
10MWest11NoNo3CA, BGCIV  
11MWest/ ME11NoNo9BGCV MT-AP6
12MWest/ME11NoNo7BGCV MT-AP6
13FWest/ME11NoNo5BGCV MT-AP6
14MRS/Alpers1YesNoNCA, BGCI (L)26% (L) 
15 FRS /Alpers24YesNo3BGCIII (L)  
16FRS /Alpers24YesNoNNCIV60% (L) 
17M +RS30NoYes6.5BG, WM, CACIV  
18M +RS4NoNoNSB, Ce ACIV (L)  
19F +RS1NoNo11.9BG, CA, BSMultiple40% (L) 
20M+(2)RS /Alpers6YesYesNCAMultiple (L)  
21F+ (2)RS /Alpers1YesYesNCAMultiple (L)  
22F +RS /Alpers24YesYesNDCeA, WM, BGMultiple (L)8% (L)POLG
23M+(3)RS /Alpers30YesYesNDCeA, WM, CAMultiple (L)61% (Mus) 8% (L)POLG
24F+(3)RS /Alpers48YesYesNDCeA, WM, CAMultiple (L) POLG
25FRS /Alpers24YesYesNDCA, BGMultiple (L)NDPOLG 
26M+(4)RS1NoNoNCA++Multiple (L)8% (L)PEO1
27F+(4)RS6NoNoNCA++Multiple (L) PEO1
28F+(4)RS2NoNoNCA++Multiple (L) PEO1
29M +RS24NoYesNDCA++CIV121% (Mus) 14% (L) 
30MRS /Alpers2YesYesNCA++CI29% (L)POLG
31FRS24NoYesNCA++CIV (L)14% (L) 
32M(5)RS4NoYesNCA++CIV21% (Mu)s 
34FRS/Alpers1NoYes2.74CA, WMCII  
35MEPC32NoYes5.4Ce A, WMCoQ CABC1
36FEPC120NoYesNDCe ACoQ21% (Mus)CABC1
37FEPC110NoNoNDCe AMultiple69% (Mus) 12% (L) 
38FEPC14NoYes2.7BG, BSCIV (L)  
39M+Myoclonic3NoNo5.8BGCI MT-ND3
40M +Myoclonic102/statNoNoNDBG, BSCI  
42M +Myoclonic48/statNoYes13Ce ACI113% (Mus) 
43F +Myoclonic90/statNoNoNDCeACI MT-TK
44M +Myoclonic240NoNoNCA occipitalCI29% (L)MT-ND5
45MMyoclonic42NoNo2.35BG, DNCI34% (L)MT-ND3
48MMyoclonic8NoNoNSB, ND, BGCIV13% (Mus) 19% (L) 
49MMyoclonic54NoNoNDBGCV MT-AP6
50FMyoclonic120NoNo3BG, DNCII SDH-A
51MMyoclonic84/statNoNoNDCeACV MT-AP6
52MMyoclonic204NoNoNDCeA, CAMultiple103% (Mus) 
53MMyoclonic10YesYesNCAMultiple (L)  
54FMyoclonic7NoYes1.2NMultiple (L)  
55F +Myoclonic/PE70NoYes6BGCV MT-AP6
56M +Myoclonic/PE82NoYes5BG,CA,WMCI+CIV MT-TL1


We identified 23 girls and 33 boys with nonoccasional and severe epileptic seizures and confirmed RCD. In the same period, 950 patients were identified in the same institution as having primary RCD. Only patients with pharmacoresistant epilepsy affecting life, motor function, or cognition were referred. Regarding this series, we cannot define any optimal strategy to identify RCD in a population of children with epilepsy. Individual data are displayed in Table 1.

Epilepsy was the presenting manifestation in 10 patients (17.5%). In all other patients it was preceded by multisystemic failure with lactic acidosis, failure to thrive, psychomotor delay, and/or other neurologic signs (ataxia, pyramidal or extrapyramidal signs, ophthalmoplegia, ptosis, retinopathy, deafness, and neuropathy). The age at onset of seizures ranged from 1 day to 20 years (median 13 months), with a peak in the first year of life (Fig. 1). Fever was the first seizure-triggering event in 11 patients (19%) at the mean age of 40 months (median 21 months). The onset of seizures was explosive in 32 patients (57%), presenting as long-lasting status epilepticus (N = 21) or an epileptic encephalopathy (11 patients).

Figure 1.

Age of onset of epilepsy.

The types of seizures consisted mainly of myoclonic seizures (massive, focal, or erratic) (n = 29), infantile spasms (n = 10), focal (n = 13), tonic (n = 5), and tonic–clonic (n = 5) seizures. Myoclonic seizures and status epilepticus (n = 29, including six with myoclonic status) were clearly overrepresented. In almost 60% of the patients, we identified more than one seizure type during the course of the epilepsy.

Monotherapy was effective in only 5%. Epilepsy was difficult to control, although a mean four antiepileptic drugs (AEDs) were administered successively or simultaneously. Sodium valproate was administered to 25 patients, one of whom developed acute liver failure a week later and underwent liver graft but died following this procedure (Table 1, Patient 22 with POLG1 mutation). Although ketogenic diet was administered to most intractable patients with good tolerability, efficacy could not be properly evaluated on retrospectively collected data. Death occurred in 23 patients (45%), a mean 21 months after seizure onset (median 9 months). It resulted from neurologic decompensation in 20 patients (95% of deaths).

Most patients (91%) exhibited MRI abnormalities, which were multiple in one-third. A major and progressive cerebral atrophy was observed in 30 patients and was isolated in 16. Diffuse white matter T2 hypersignal was present in nine patients. Basal ganglia involvement (20 patients), the most frequent feature, was often combined with atrophy of subtentorial structures. The cerebellum was involved in 12 patients: 5 had severe cerebellar atrophy alone, 3 had cerebellar atrophy associated with subtentorial abnormalities, and 4 exhibited T2 hypersignal in the dentate nuclei. H-MRS was performed for the 10 most recent patients and disclosed lactate peaks in the basal ganglia or cerebellum in only five patients.

With respect to the characteristics of epilepsy (age of onset, seizure type, EEG, and course), six groups could be identified:

  • (1) Status epilepticus complicating multivisceral deficiency (two patients); (2) Early myoclonic encephalopathy with suppression bursts (three patients); (3) West syndrome including spasms in clusters with hypsarrhythmia and psychomotor regression (eight patients); (4) Refractory status epilepticus lasting several days or weeks and ending with either death or major neurologic deterioration until a relapse several months later (21 patients); (5) Epilepsia partialis continua (EPC) on one or eventually both sides (four patients); and (6) Epilepsy in which the major seizure type was myoclonic (18 patients), consisting of either daily brief massive myoclonus, or very frequent erratic jerks involving the distal parts of the limbs and the mouth (12 patients), eventually reaching myoclonic status epilepticus.

Neonatal multivisceral deficiency (Group I)

Two neonates presented with refractory status epilepticus at 2 and 6 days of age, respectively. In one patient (Patient 1), status epilepticus was preceded by multisystemic failure, severe lactic acidosis, and abnormal signal of the thalami on transfontanellar ultrasonography. He died on day 3. The other patient (Patient 2) had heart failure with hypertrophic cardiomyopathy, but both EEG and ultrasonography were normal until he developed multifocal status epilepticus lasting 24 h. He died on day 10 of renal and cardiac failure. The clinical condition was such that no brain MRI could be performed for these two patients. Both were diagnosed with multiple deficiencies of respiratory chain complexes. No molecular abnormality could be identified.

Neonatal myoclonic encephalopathy (Group II)

Three patients (Patients 3–5) presented with severe hypotonia, irritability, and poor eye contact from birth. The first epileptic manifestations were massive myoclonic jerks noticed at the ages of 2 days, 1 month, and 3 months, respectively. EEG showed a suppression-burst pattern. Diffuse cerebral atrophy was associated with white matter signal abnormality (two patients) or callosal hypoplasia (one patient). In one patient (Patient 5), evolution was marked by massive psychomotor delay and extremely refractory myoclonic jerks that persisted until the patient died at 8 years of age. In the two remaining patients (Patients 3 and 4), epileptic spasms were noted at 8 months and still persisted at the time of the study, at respectively 4 and 18 years. EEG showed suppression-bursts during sleep in one patient and multifocal discharges with a very slow high-amplitude background activity during wakefulness in two patients. They had deficiency in complexes IV (two patients) or I (one patient), and no patient had DNA depletion.

Infantile spasms (Group III)

Infantile spasms in clusters were observed in eight patients, beginning at 8.5 months (median 6 months). Flexor spasms were the first epileptic manifestation in all patients except two, in whom they were preceded by tonic seizures (Patients 8 and 9), associated with myoclonic seizures in one of them (Patient 13). For all patients but one, psychomotor delay had been noticed before the onset of spasms, and all patients presented with definite psychomotor regression after onset of spasms.

Ictal EEG showed clusters of high-amplitude slow waves combined with low-amplitude fast rhythms, consistent with the usual pattern of epileptic spasms. Interictal EEG showed hypsarrhythmia.

MRI showed hypersignal in the basal ganglia for four patients (Patients 10–13), and diffuse cerebral atrophy for five. Cerebral atrophy was associated with increased signal of the white matter for one and dentate nuclei hypersignal for another patient.

Spasms were controlled by vigabatrin alone in three patients or combined with steroids (three patients) or clobazam (two patients). Psychomotor improvement was observed following cessation of spasms except for one patient, who experienced ongoing global neurologic deterioration leading to death, despite the control of spasms.

The RCD consisted of the MT-AP6 mutation (three patients) and of deficiencies of complexes I (two patients), IV (two patients), and II (one patient).

Refractory or recurrent status epilepticus (Group IV)

In 21 patients with preexisting psychomotor delay of variable degree, epilepsy started with status epilepticus consisting of generalized or unilateral clonic seizures. The age at onset ranged from 3 weeks to 10 years (mean 34 months; median 21 months).

Status epilepticus consisted either of nearly continuous polymorphous motor seizures of continuous, more or less rhythmic bilateral jerks, or of jerks affecting alternatively both sides. Oculoclonus, a frequent video-EEG discovery, was easily overlooked and its incidence can therefore not be determined.

Ictal EEG consisted of migrating focal discharges involving nearly continuously both hemispheres, mainly the posterior areas (Fig. 2A), each lasting 2–3 min and followed by very poor or flat recording (Fig. 2B). Video recording showed that these discharges corresponded to clonic seizures of the face and one upper limb, eventually switching to the other side. Other seizures comprised sequences lasting for half an hour or more with lateral oculoclonia that could end in a focal clonic seizure. Interictal recordings showed high amplitude, very slow polyrhythmic activity, with more or less periodic polyspikes, mainly in the posterior areas (Fig. 3). Repeat recordings revealed progressive impoverishment of the tracing, culminating in bursts of suppression of the cerebral activity (Fig. 4).

Figure 2.

(A, B) Eight-year-old boy with mitochondrial DNA (mtDNA) depletion (Patient 29) (Group IV). Recorded seizure at onset (Fig 4A) and end (Fig 4B) with both occipital discharges affecting successively right and left hemispheres combined with oculoclonia (artifacts on Fp2 and Fp1); generalized spike and waves at the end of the seizure then flattening.

Figure 3.

Eight-year-old boy with mitochondrial DNA (mtDNA) depletion a few days before death (Patient 29) (Group IV). Interictal electroencephalography (EEG) tracing shows very poor background activity with periodic slow complexes on frontal areas.

Figure 4.

Two-year-old girl (Patient 34) with periodic spike activity in both occipital and right frontal areas (Group IV).

MRI showed isolated and severe cortical atrophy (10 patients), cerebellar and cortical atrophy (six patients), white matter hypersignal (six patients), and basal ganglia involvement (six patients). The course of the epilepsy was severe, although not uniform: Eight patients presented with an extremely severe and prolonged status epilepticus refractory to all AEDs with progressive drowsiness and coma, leading to death within one week to 3 months in eight patients. In the 13 other patients, the initial status resolved, but repeat episodes of status epilepticus occurred, with severe psychomotor regression following each episode. Various seizure types including erratic myoclonic jerks or EPC also refractory to AEDs persisted between the episodes of status epilepticus.

A variable degree of liver dysfunction was found in 10 patients, with one terminal hepatic failure. Death occurred in 13 patients from 1 week to 21 months (mean 6 months) following the onset of epilepsy.

In 13 patients, RCD could be identified in the liver only, with negative investigations in muscle and fibroblasts. A deficit of complexes I (two patients), IV (seven patients), III (one patient), or II (one patient) was identified. For the remaining 10 patients, there were multiple complex deficiencies. Severe mtDNA depletion (mtDNA copy number <25% of control values) was searched for in 10 patients and present in 7, but it affected only the liver. mtDNA depletion was associated with mutations in POLG1 for four patients and in PEO1 for three others.

Epilepsia partialis continua (Group V)

After an initial status epilepticus lasting from 1–6 days, four patients (Patients 35–38) developed EPC that consisted of continuous jerks on one side of the body without alteration of consciousness. On EEG, slowing of background activity predominated on the contralateral side, but there were no spikes. Creatine phosphokinase values were elevated in two patients, ranging from 600–900 IU. The first jerks occurred very suddenly at the mean age of 4.5 years (median 3.8 years), and were triggered by fever in two patients. Psychomotor delay had preceded the first seizures in all the patients and was associated with cerebellar ataxia and severe cerebellar atrophy on MRI. During the episode of EPC, diffusion-weighted MRI images showed very limited areas with high diffusion designating precisely the sulci involved in the paroxysmal activity. MRI showed atrophy of these areas following cessation of EPC.

Two patients with coenzyme Q10 deficiency were identified with CABC1 mutation (Patients 35 and 36). One patient with complex IV deficiency had severe mtDNA depletion disclosed only in the liver (Patient 37). Another patient (Patient 38) had complex IV deficit in the liver but depletion could not be searched because we had no more liver sample.

Myoclonic epilepsy (Group VI)

Eighteen patients presented with myoclonus as the main seizure type. Onset ranged from one year to adulthood. Although the predominant seizure type in the course of the disease was massive myoclonus, it was the first manifestation in only half of the patients. Other types of seizures including erratic myoclonus, focal motor seizures, myoclonic absences, or tonic seizures had previously occurred in the course of the disease, in association or more often following the first massive jerks. Six patients developed recurrent myoclonic status epilepticus (Fig. 5). Only one of them (Patient 43) with MT-TK mutation had photosensitivity with intermittent light stimulation induced spikes. MRI showed T2/FLAIR (fluid-attenuated inversion recovery) basal ganglia hypersignal (eight patients), cerebellar atrophy (five patients), and T2/FLAIR dentate nuclei hypersignal (three patients). Basal ganglia were involved irrespective of the age of onset, whereas cerebellar involvement was disclosed only in patients with epilepsy onset in the middle of the first decade. Myoclonic seizures were pharmacoresistant. Six patients died with neurologic degradation and coma.

Figure 5.

Myoclonic jerks recorded on surface electromyography (EMG) of deltoid muscles (EMG1 right, EMG2 left) during myoclonic status in a 16-year-old girl (Patient 26) with myoclonic epilepsy with ragged-red fibers (MERRF) (Group VI). Bilateral subcontinuous central spikes or spike and waves in both central areas, associated with some diffuse bursts of spikes.

Eight patients with complex I, three with complex V, two with complex IV, one with complex II, one with complexes I+IV, and three with multiple deficiencies were identified. mtDNA mutations were found in 45% of the patients: 3 MT-AP6, 2 MT-ND3, 1 MT-TK, 1 MT-ND5, and 1 MT-TL1 (Table 1). Only one patient had significant mtDNA depletion.


The published series combining RCD and epilepsy involve mainly adult patients with mtDNA mutations, and focal epilepsy predominates except for MERRF (Canafoglia et al., 2001). In contrast, the only two reported pediatric series mention a great predominance of generalized epilepsy syndromes (Lee et al., 2008; Khurana et al., 2008). The present study confirms this point and provides additional characteristics of epilepsy in children: It occurs within the first year of life in two-thirds of the patients, is refractory to drug treatment except for infantile spasms, and carries mostly a negative prognosis. The occurrence of intractable seizures is constantly associated with severe neurologic deterioration, as mentioned by Khurana et al. (2008). Half the patients die within the year following the onset of epilepsy. The condition can be acute and rapidly lethal through episodes of status epilepticus, it corresponds to age-related epilepsy syndromes known to occasionally result from inborn errors of metabolism, or it expresses a predominant involvement of the rolandic and posterior areas. In fact, there seems to be a wide spectrum of clinical severity ranging from treatable West syndrome to lethal status epilepticus, and some kind of relationship to biochemical and molecular findings appears, with multiple complex deficits and mtDNA depletion corresponding to the worst clinical condition.

We identified six groups according to clinical and EEG characteristics

In catastrophic neonatal forms (Group I), seizures reveal diffuse parenchymal failure. It is not clear whether seizures consist of epilepsy or are occasional events, since the patients die within a few days of onset of the symptoms.

In neonatal myoclonic encephalopathy (Group II), the course of epilepsy is chronic, evolving to infantile spasms, then becoming multifocal, with severe psychomotor impact and acquired microcephaly. Although myoclonic neonatal encephalopathy is known to result from inborn errors of metabolism, mitochondriopathy is not usually mentioned. It is noteworthy that RCD in the context of this non–life-threatening condition involves a single mitochondrial complex.

Infantile spasms (Group III) are combined with the MT-AP6 mutation in half the patients and basal ganglia T2 hypersignal contributes to the etiologic diagnosis (Desguerre et al., 2003). Mitochondrial disorders are an easily overlooked etiology of infantile spasms (Shah et al., 2002). Similar to neonatal myoclonic encephalopathy, RCD exhibits a single complex defect.

In refractory status epilepticus (Group IV) the prognosis is very poor with severe cortical atrophy and hepatic failure described as Alpers syndrome (Kollberg et al., 2006). This is the most common epilepsy syndrome in our series, but half the patients never exhibited liver failure and when it occurred, it was most often late in the course of the disease. The ultimate disappearance of EEG basal activity can be accounted for by the complete depopulation of cortical neurons, with apoptosis of the few remaining cells (Harding, 1990).

In this context, MRI shows mainly massive cortical atrophy, whereas basal ganglia hypersignal involves less than one-fourth of the 21 patients. Therefore, at onset this condition raises the issue of refractory status epilepticus of unknown cause. EEG is most helpful. The presence of rhythmic polyspikes in posterior areas has been stressed (Boyd et al., 1986; Wolf et al., 2009) and the occipital predominance of both ictal and interictal anomalies rather point to progressive metabolic encephalopathies as in Lafora disease (Villanueva et al., 2006) and ceroid-lipofuscinosis (Striano et al., 2007). These characteristics permit the distinguishing of Alpers disease from different conditions according to age: in infancy, from the syndrome of migrating partial seizure in infancy (Coppola et al., 1995), and in school age from a condition quoted as devastating epileptic encephalopathy in school aged children (DESC) (Mikaeloff et al., 2006). Although half the patients exhibit neither clinical nor biologic signs of hepatic involvement, it is only in the liver that mtDNA depletion can be identified (Panetta et al., 2005). Our findings contrast with the only reported pediatric series that mentions a single case of Alpers syndrome among 48 cases of epilepsy resulting from mitochondriopathy (Lee et al., 2008). This may result from the mode of selection of the patients, which was mainly based on muscle biopsy. Mitochondrial DNA depletion was first reported; then polymerase gamma 1 (POLG1) was identified as the gene the most frequently involved (Nguyen et al., 2005a). In a series of 26 patients with POLG1 mutations, 22 exhibited epilepsy, most often in infancy or between 2 and 4 years of age, the majority with an occipital EEG focus (Tzoulis et al., 2006).

In EPC (Group V), epilepsy begins very suddenly with intractable focal clonic jerks, in patients known to have previous cerebellar ataxia. Therefore, the initial episode presents as less severe than for patients of Group IV. Nevertheless, MRI shows that the rolandic area is damaged by this acute onset. In two patients, a defect of the coenzyme Q10 metabolism pathway could be demonstrated (Boitier et al., 1998) and the molecular defect, a CABC1 mutation identified (Mollet et al., 2008). EPC has been reported also in combination with defects in the respiratory chain (Riquet et al., 2007) and with POLG1 mutations (Tzoulis et al., 2006).

In myoclonic epilepsy (Group VI) half the patients exhibit basal ganglia and/or cerebellar atrophy. Cerebellar atrophy is a well-known component of progressive myoclonic epilepsy, particularly Lafora disease (Villanueva et al., 2006), ceroid-lipofuscinosis (Striano et al., 2007), and Unverricht-Lundborg (Mascalchi et al., 2002). Half the patients had mtDNA mutation and the onset was after 4 years in two-thirds.

It is striking that we encountered no patient with Landau-Kleffner or Lennox-Gastaut syndromes in the present series, in contrast with the only other pediatric series that reports respectively 4.2–25% (Lee et al., 2008).

Diagnostic difficulties

In the context of status epilepticus, the highest proportion of our series, diagnosis of RCD remains challenging. Seizures are rarely the first expression of the disease. They are frequently preceded by one or more symptoms (i.e., failure to thrive, psychomotor delay, and ataxia). CSF examination and spectroscopy fail to disclose lactate, and muscle biopsy is negative. Therefore, liver biopsy is the only means of diagnosis (Nguyen et al., 2005b; Panetta et al., 2005). In another series, deoxyguanosine kinase or POLG1 mutations affected 11 of 32 patients with liver involvement, and all 7 patients with Alpers syndrome (Sarzi et al., 2007a). The clinical and EEG pattern, nevertheless, is quite specific and offers no major alternative. Data remain too scarce to determine whether the search of mutations in some hot spot could permit the avoidance of liver biopsy.

Therapeutic issues

The responsibility of valproate in live failure related to RCD is often claimed. One case of fatal hepatic failure with Alpers disease is on record, in addition to the one of our series (Tzoulis et al., 2006). On the other hand, there is high risk of epilepsy worsening following drug withdrawal. Considering that hepatic failure has been reported exclusively in patients with mtDNA depletion, it seems wise to advise valproate withdrawal in these patients only.

Levetiracetam, which seems to have some protective effect on mitochondria (Lagrue et al., 2007) and may give some transient benefit in MERRF disease (Mancuso et al., 2006), could be an alternative.

The benefit of ketogenic diet is highlighted in one series in which half the patients stopped having seizures (Lee et al., 2008). Indeed, it could add antiepileptic effect to alternative sources of energy. However, although some of our patients seemed to benefit from the ketogenic diet, no dramatic improvement occurred. This could be due to the different range of severity of the two series, since a large proportion of our patients exhibited status epilepticus and one-third had Alpers syndrome.

Mechanisms of epilepsy and impact on brain function

The observed variability of the clinical expression raises the question of the relationship between epilepsy and RCD across age ranges. Our findings permit only speculation based on reported experimental data and clinical observation. Therefore, in diseases affecting brain energy supply, particularly mitochondriopathies, seizures seem to superimpose onto the more or less tolerable consequences of chronic energy defect the consequences of acute failure. Thus two vicious cycles are combined: energy providing defect due to mitochondriopathy and worsening of the mitochondrial dysfunction by the epilepsy. Both contribute to neuronal dysfunction, triggering epileptogenicity and eventually cell death.

Seizure-induced mitochondrial dysfunction

Ictal functional imaging investigations have shown that in the course of epileptic seizures, brain metabolism doubles in order to cope with the requirements of the discharge (Ryding et al., 1988). Experimental data point to the central role of mitochondria in providing this increased energy need. Therefore, epilepsy generates alteration of the fine-tune coupling between mitochondrial function and neuronal activity (Kann & Kovacs, 2007). In temporal lobe epilepsy, the CA3 region discloses marked mitochondrial abnormalities (Kunz, 2002). Complex I deficiency was observed following seizures produced by intracerebral infusion of dl-homocysteine acid in immature rats (Folbergrova et al., 2007).

Energy failure facilitates the seizure occurrence

Intractable epilepsy in the course of inborn errors of metabolism often contributes to the severity of the disease. This is the case for Menkes disease (Bahi-Buisson et al., 2006), non ketotic hyperglycinemia (Tada & Kure, 1993), pyridoxine dependency (Nabbout et al., 1999), and for glut I (Leary et al., 2003) and creatine (Stromberger et al., 2003) deficiencies. All these conditions share either severe energy failure (Menkes, glut I, and creatine deficiencies) or a dramatic excess in excitatory mechanisms (hyperglycinemia and pyridoxine dependency).


Various features should call attention to possible mitochondriopathy. Myoclonus, infantile spasms, or oculoclonia in a child with previous psychomotor delay or failure to thrive, with involvement of basal ganglia, cerebellum, or cortex, is particularly suggestive. RCD study including search of mtDNA depletion in the liver is highly contributory. Refractory epilepsy indicates a severe turn in the disease and high risk for rapid fatal outcome, particularly in the context of multiple complex defects.


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None of the authors have any conflict of interest to disclose.